Cryopyrin/NLRP3 Signaling in Inflammation and Innate Immunity

Cryopyrin/NLRP3 信号在炎症和先天免疫中的作用

• 批准号: 10308668
• 负责人: Gabriel Nunez
• 金额: $ 39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10308668
• 关键词: Actins; Alzheimer' s Disease; Atherosclerosis; Bacterial Toxins; Biochemical; CASP1 gene; Development; Diabetes Mellitus; Disease; Event; Gouty Arthritis; Grant; In Vitro; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-18; Link; Mediating; Molecular; Motor; Natural Immunity; Particulate Matter; Pathogenesis; Phosphorylation; Phosphotransferases; Proteins; Role; Signal Transduction; Silicosis; Stimulus; base; biological systems; in vivo; insight; novel therapeutic intervention; prevent; response

The NLRP3 inflammasome is a critical platform for the activation of caspase-1 and secretion of biologically active IL-1β and IL-18 in response to bacterial toxins, particulate matter and certain endogenous stimuli. Furthermore, aberrant activation of NLRP3 has been linked to the pathogenesis of several acquired inflammatory disorders including gouty arthritis, silicosis, atherosclerosis, diabetes and Alzheimer’s disease. Although much progress has been made about the stimuli and cellular events that activate the NLRP3 inflammasome, a major gap in the field is the identification of molecules that are required for NLRP3 activation and the mechanism of caspase-1 activation in response to NLRP3 activating stimuli. The Nek7 kinase was identified during the last cycle of the grant as a critical factor required for NLRP3 activation in response to a wide array of stimuli in vitro and in vivo. Nek7 was shown to act downstream of K+ efflux to activate NLRP3. However, the mechanism by which K+ efflux activates NLRP3 via Nek7 remains unknown. Furthermore, the molecular events by which NLRP3 activates caspase-1 via the adaptor ASC to induce ASC oligomerization and ASC speck formation are poorly understood. In this renewal application, we propose studies in three specific Aims to (i) determine how K+ efflux activates the NLRP3 inflammasome through the kinase Nek7 using biochemical and in vivo approaches; (ii) identify factors that regulate the phosphorylation of Nek7 to mediate the activation of NLRP3 and (iii) further characterize the role of actin-based motor proteins in the mechanism of ASC-mediated inflammasome activation. Understanding how NLRP3 is activated is expected to provide critical insight into the role of the inflammasomes in different biological systems which will aid the development of new therapeutic approaches to prevent and/or treat inflammasome-associated diseases.

NLRP3炎性小体是激活caspase-1和分泌caspase-1的重要平台